AsianScientist (Sep. 21, 2015) – Researchers at the University of Tokyo have demonstrated a new biosynthetic methodology to rationally design the polyketide carbon skeleton of the antibiotic antimycin. The findings, published in Angewandte Chemie, open the door to the biosynthetic production of ‘unnatural’ natural products, which will contribute to medicinal chemistry.
The synthesis of pharmaceuticals products is mostly performed by organic synthesis. Recently, however, much attention has been focused on synthetic biology, which produces valuable compounds by enzymatic reaction and microbial fermentation. However, there are still only limited ways to rationally design a target compound by synthetic biology. Thus the invention of methodologies that enable free molecular design will be a major advancement.
The research group of graduate student Zhang Lihan and Professor Abe Ikuro at the University of Tokyo Graduate School of Pharmaceutical Sciences has successfully introduced an aromatic substitution into the carbon skeleton of a polyketide antibiotic, antimycin by synthetic biology.
The research group focused on an enzyme, crotonyl-CoA carboxylase/reductase, which supplies building blocks of the carbon skeleton, and enhanced the catalytic property of the enzyme to provide unnatural building blocks that are not seen in natural poliketides. Furthermore, by introducing the engineered enzyme into biosynthesis of antimycin, unnatural compounds with novel carbon skeletons bearing aromatic residues were produced.
“One of the features of natural products is that they utilize common strategies to build diverse molecules, and hence this result could be theoretically applicable to the biosynthesis of many natural products,” says Abe.
By diversifying the structures of natural products that are hard to synthesize, the findings demonstrated here will lead to developments in drug discovery.
The article can be found at: Zhang et al. (2015) Rational Control of Polyketide Extender Units by Structure-Based Engineering of a Crotonyl-CoA Carboxylase/Reductase in Antimycin Biosynthesis.
———
Source: Universtiy of Tokyo.
Disclaimer: This article does not necessarily reflect the views of AsianScientist or its staff.
